The neurophysiological effect of NMDA-R antagonism of frontotemporal lobar degeneration is conditional on individual GABA concentration

Abstract

There is a pressing need to accelerate therapeutic strategies against the syndromes caused by frontotemporal lobar degeneration, including symptomatic treatments. One approach is for experimental medicine, coupling neurophysiological studies of the mechanisms of disease with pharmacological interventions aimed at restoring neurochemical deficits. Here we consider the role of glutamatergic deficits and their potential as targets for treatment. We performed a double-blind placebo-controlled crossover pharmaco-magnetoencephalography study in 20 people with symptomatic frontotemporal lobar degeneration (10 behavioural variant frontotemporal dementia, 10 progressive supranuclear palsy) and 19 healthy age- and gender-matched controls. Both magnetoencephalography sessions recorded a roving auditory oddball paradigm: on placebo or following 10 mg memantine, an uncompetitive NMDA-receptor antagonist. Ultra-high-field magnetic resonance spectroscopy confirmed lower concentrations of GABA in the right inferior frontal gyrus of people with frontotemporal lobar degeneration. While memantine showed a subtle effect on early-auditory processing in patients, there was no significant main effect of memantine on the magnitude of the mismatch negativity (MMN) response in the right frontotemporal cortex in patients or controls. However, the change in the right auditory cortex MMN response to memantine (vs. placebo) in patients correlated with individuals’ prefrontal GABA concentration. There was no moderating effect of glutamate concentration or cortical atrophy. This proof-of-concept study demonstrates the potential for baseline dependency in the pharmacological restoration of neurotransmitter deficits to influence cognitive neurophysiology in neurodegenerative disease. With changes to multiple neurotransmitters in frontotemporal lobar degeneration, we suggest that individuals’ balance of excitation and inhibition may determine drug efficacy, with implications for drug selection and patient stratification in future clinical trials.

GABAergic modulation of beta power enhances motor adaptation in frontotemporal lobar degeneration

“…29, 36, 72 While we cannot show the GABA deficit of the specific participants in our study, others have shown a reduction in frontal cortical GABA in people with PSP and bvFTD, 4, 29 in proportion to cognition (Perry et al, 2022, SI Fig. 3 12 ). The pharmacological effects on beta oscillations may be drug-specific, and we note for example that propofol, a GABAa receptor modulator and agonist, does not have comparable effects on movement related beta oscillations.…”

“…6–8 In some people with progressive supranuclear palsy (PSP) motor and behavioural impairments respond transiently to GABAergic modulation. 9, 10 Trials of memantine, a non-competitive antagonist at NMDA and other receptors had no generalised efficacy, 11, 12 but clinical responses may also depend on the severity of baseline deficits. 12…”

“…9, 10 Trials of memantine, a non-competitive antagonist at NMDA and other receptors had no generalised efficacy, 11, 12 but clinical responses may also depend on the severity of baseline deficits. 12…”

“…[6][7][8] In some people with progressive supranuclear palsy (PSP) motor and behavioural impairments respond transiently to GABAergic modulation. 9,10 Trials of memantine, a non-competitive antagonist at NMDA and other receptors had no generalised efficacy, 11,12 but clinical responses may also depend on the severity of baseline deficits. 12 We propose a strategic approach that links pharmacological modulation to behavioural effects via their underlying neurophysiological mechanisms, including physiological responses in prefrontal cortical circuits.…”

The role of GABA in semantic memory and its neuroplasticity

“…Extreme levels of GABA can be found in studies with dementia patients and pharmacological studies with GABA agonists. Recent studies have reported decreased GABA levels in Alzheimer's disease 72,73 and frontotemporal dementia 74,75 in relation to their cognitive impairments such as memory and language. In fact, GABA agonists like midazolam have been found to improve a verbal generation in anxiety patients by increasing GABAergic function 76 .…”